Few methods are known for the preparation of hydroxy halide and organooxy halide alkylating agents. Hydroxymethylaryl halides have been prepared from the corresponding aryldimethanols by treatment with hydrogen halides. The reported yields of the desired compounds from aryldimethanols having two equivalent functional groups are generally about 50% or less. For example, Traylor and Ware in J. Amer. Chem. Soc. 89, 2304-2316 (1967) report only a 16% yield of p-hydroxymethylbenzyl chloride from 1,4-benzenedimethanol (p-xylene-.alpha.,.alpha.'-diol). Yamato et al. in Synthesis, pp. 1014-1015 (December, 1982) report a 53% yield of o-bromomethylbenzyl alcohol from 1,2-benzenedimethanol.
A 90% yield of 4-hydroxymethyl-2,3,4,5-tetrafluorobenzyl bromide obtained from 1,4-bis(hydroxymethyl)-2,3,4,5-tetrafluorobenzene by treatment with 48% hydrobromic acid was reported by Costello and Milner in Synthetic Communications, 17, 219-221 (1987). However, it has since been shown that treatment of benzenedimethanols lacking nuclear halogen substituents shows no particular selectivity, and accordingly, the unusually high yield in this isolated example is believed to be an anomaly due to insolubility of the monohalogenated product in the reaction media.
Lam et al., PCT International Publication Number WO 93/07128 discloses cyclic carbonyl compounds and derivatives thereof which are useful as human immunodeficiency virus (HIV) protease inhibitors for the treatment of HIV infection. The compounds disclosed in WO 93/07128 include cyclic urea compounds of the formula below where W may be --N(R.sup.22)C(.dbd.O)N(R.sup.23)--. ##STR1## WO 93/07128 discloses compounds wherein groups R.sup.5 and R.sup.6 may be --O-MEM (MEM=2-methoxyethoxymethyl), --O-SEM (SEM=2-(trimethylsilyl)ethoxymethyl) or --O-MOM (MOM=methoxymethyloxy) or may be taken together to form an acetonide ring. WO 93/07128 also discloses processes for the preparation of alkylated cyclic ureas. The processes of the present invention provide improved alkylating agents and processes for the alkylation of the urea nitrogens to obtain such cyclic urea HIV protease inhibitor compounds.
As disclosed in WO 93/07128, such cyclic urea compounds, which may be made using the processes of the present invention are non-peptidic, low molecular weight, orally bioavailable compounds useful as inhibitors of HIV protease and for the treatment of HIV infection. The HIV protease inhibitory activity of the cyclic urea can be increased by two to three orders of magnitude by alkylating one or both of the urea nitrogens.
Consequently, a need exists for efficient and cost-effective methods for the preparation of the cyclic urea HIV protease inhibitor compounds of WO 93/07128. The present invention provides processes for the preparation of hydroxy halide and organooxy halide alkylating agents in high yields from readily available starting materials. The alkylating agents of the present invention are effective alkylating agents for the alkylation of cyclic urea nitrogens.